Brain-derived extracellular vesicles circUsp32 polarized macrophages causing acute kidney injury after traumatic brain injury

  • Sci Adv. 2025 Nov 28;11(48):eadz1243. doi: 10.1126/sciadv.adz1243.
Jiayuanyuan Fu  1 ,  Jingheng Wu  1 ,  Mengran Du  2 ,  Xu Wang  1 ,  Qi Shi  1 ,  Yehong Fang  1 ,  Yu Lan  1 ,  Qiaoli Wu  1  3 ,  Guobin Zhang  1  3 ,  Lixia Xu  1  3 ,  Hua Yan  1  3
Affiliations
  • 1. Huanhu Hospital Affiliated to Tianjin Medical University, Tianjin Medical University, Tianjin 300070, China.
  • 2. Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuanjiagang, Yuzhong District, Chongqing 400016, China.
  • 3. Tianjin Key Laboratory of Cerebral Blood Flow Reconstruction and Head and Neck Tumor New Technology Translation, Tianjin Huanhu Hospital, Tianjin 300350, China.
PMID: 41296848 DOI: 10.1126/sciadv.adz1243
Abstract

Brain-kidney cross-talk following traumatic brain injury (TBI) can induce acute kidney injury (AKI), but mechanisms remain unclear. Extracellular vesicles derived from injured brain tissue (TBI-EVs) may mediate brain-kidney interactions. In vivo experiments demonstrated that TBI-EVs causes AKI by promoting pro-inflammatory macrophage polarization. TBI-EVs markedly increased AKI markers and proportion of pro-inflammatory-polarized macrophages. Mechanistically, transcriptomics of TBI-EVs revealed high circUsp32 expression. Subsequent in vitro assays showed that circUsp32 competitively binds to the SH2 domain of suppressor of cytokine signaling 1 (Socs1), affecting interferon regulator factor 7 (IRF7) ubiquitination and promoting pro-inflammatory polarization. CircUsp32 knockdown reduced pro-inflammatory polarization and alleviated AKI in TBI mice. In addition, circUsp32 is homologous to hsa_circ_0044940, which may serve as a predicted biomarker of AKI after TBI. Notably, AKI following TBI may contribute to neuroinflammation via uremic toxins. Collectively, these findings suggest that circUsp32 mediates macrophage polarization through the Socs1/IRF7 axis and could be a potential biomarker for AKI following TBI.

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